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J. Biol. Chem., Vol. 282, Issue 28, 20116-20123, July 13, 2007

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SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B^*

From the Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521

The SWI/SNF chromatin remodeling complex plays a critical role in the coordination of gene expression with physiological stimuli. The synthetic enzymes ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase are coordinately regulated to ensure appropriate deoxyribonucleotide triphosphate levels. Particularly, these enzymes are actively repressed as cells exit the cell cycle through the action of E2F transcription factors and the retinoblastoma tumor suppressor/p107/p130 family of pocket proteins. This process is found to be highly dependent on SWI/SNF activity as cells deficient in BRG-1 and Brm subunits fail to repress these genes with activation of pocket proteins, and this deficit in repression can be complemented, via the ectopic expression of BRG-1. The failure to repress transcription does not involve a blockade in the association of E2F or pocket proteins p107 and p130 with promoter elements. Rather, the deficit in repression is due to a failure to mediate histone deacetylation of ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase promoters in the absence of SWI/SNF activity. The basis for this is found to be a failure to recruit mSin3B and histone deacetylase proteins to promoters. Thus, the coordinate repression of deoxyribonucleotide triphosphate metabolic enzymes is dependent on the action of SWI/SNF in facilitating the assembly of repressor complexes at the promoter.

Received for publication, February 16, 2007 , and in revised form, May 14, 2007.

^* This work was supported by NCI, National Institutes of Health Grant CA104213 (to E. S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 3125 Eden Ave., Cincinnati, OH 45267-0521. Tel.: 513-558-8885; Fax: 513-558-4454; E-mail: erik.Knudsen{at}uc.edu.

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				M. D. Kaeser, A. Aslanian, M.-Q. Dong, J. R. Yates III, and B. M. Emerson BRD7, a Novel PBAF-specific SWI/SNF Subunit, Is Required for Target Gene Activation and Repression in Embryonic Stem Cells J. Biol. Chem., November 21, 2008; 283(47): 32254 - 32263. [Abstract] [Full Text] [PDF]